Combination chemotherapy in sequence for the treatment of L1210 leukemia.

In the studies presented L1210 leukemia was used to show that various equipotent combinations of two drugs can be freely substituted for each other during the course of sequential treatment with other drugs and that the order of administration will influence the therapeutic re sponse to sequential treatment with various drug combi nations. Mice inoculated i.p. with L1210 ascites tumor cells were treated with 4 -demethylepipodophyllotoxin-9(4,6-O-2-thenylidene-/3-D-glucopyranoside), 1-/3-o-arabinofuranosylcytosine plus methotrexate, or Adriamycin plus cyclophosphamide in various dosages and se quences. Three ratios of dosages for each two-drug com bination were selected to produce equivalent prolonga tion of life span when administered on Days 1, 4, and 7. When these two-drug combinations were used for sequen tial treatment with 4'-demethylepipodophyllotoxin-9-(4,6O-2-thenylidene-ß-D-glucopyranoside on Day 1, 1-/3-o-arabinofuranosylcytosine plus methotrexate on Day 4, and Adriamycin plus cyclophosphamide on Day 7, each of the three ratios of dosages for the two two-drug combinations was equivalent in prolonging the lives of mice inoculated with L1210 tumor cells. When the sequence of administra tion was varied, marked differences were observed in the effectiveness of treatment. These observations indicate that a variety of dosages of oncolytic drugs can be used to produce equivalent therapeutic response and that the order of administration may determine the overall effec tiveness of sequential multiple-drug therapy.